Abstract
Title:A pragmatic pilot randomized phase II controlled trial of Prothrombin Complex Concentrates
(PCC) versus Fresh Frozen Plasma (FFP) in adult patients who are Undergoing Heart
Surgery (PROPHESY)
Dr Laura Green, Blizard Institute, Queen Mary University of London, NHS Blood and Transplant and
Barts Health NHS Trust. 4 Newark St, Whitechapel, London E1 2AT [email protected]
Mr Neil Roberts,* St Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE. [email protected]
Jackie Cooper, Barts Cardiovascular Clinical Trials Unit (CVCTU), William Harvey Research Institute,
Heart Centre, Barts and The London School of Medicine, Queen Mary University of London,
Charterhouse Square, London EC1M 6BQ [email protected]
Jane Field, Barts Cardiovascular Clinical Trials Unit (CVCTU), William Harvey Research Institute,
Heart Centre, Barts and The London School of Medicine, Queen Mary University of London,
Charterhouse Square, London EC1M 6BQ [email protected]
Dr Andrew Klein, Papworth Hospitals NHS Foundation Trust, Papworth Everard, Cambridge, CB23 3RE [email protected]
Dr Seema Agarwal, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL [email protected]
Professor Simon Stanworth, Oxford University Hospitals NHS Foundation Trust, Headley Way, Oxford, OX3 9BQ.
[email protected]
Professor Atholl Johnston, William Harvey Research Institute, Heart Centre, Barts and The London School of
Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ. [email protected]
Dr Vivienne Monk, Barts Cardiovascular Clinical Trials Unit (CVCTU), William Harvey Research Institute,
Heart Centre, Barts and The London School of Medicine, Queen Mary University of London,
Charterhouse Square, London EC1M 6BQ [email protected]
Professor Ben O’Brien, St Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE
Outcomes Research Consortium, Cleveland Clinic, OH, USA. [email protected]
Abstract
Background: Fresh Frozen Plasma (FFP) is the accepted standard treatment for clotting factor replacement
in bleeding patients during, or immediately after cardiac surgery. In the United Kingdom (UK) prothrombin complex concentrate (PCC) is not licensed in this setting although it
is being used in Europe, because it has a higher concentration of clotting factor
levels, and it can be administered rapidly and in small volume, resulting in less
volume overload during cardiac surgery.
Methods: PROPHESY is a pragmatic single-centre, open-label, randomized, controlled pilot
trial that will assess whether it is feasible to perform a large trial in the future
that will compare PCC versus FFP in patients who are bleeding (not on warfarin) and
who require blood transfusion. Over a 15-month period, 50 patients will be randomized
to PCC versus FFP if they develop active bleeding within 24 hours of cardiac surgery, and for whom the
clinician has decided to administer FFP for treatment of bleeding. Standard laboratory and Point-of-Care assessments will be performed as per routine
practice, and additional research blood samples will be taken at three time-points
to assess haemostasis. Subjects will be assessed daily up to hospital discharge or
30 days or death (whichever occurs first) and will be followed up for 90 days after
surgery to assess for thromboembolic complications, and hospital re-admission since
discharge. Quality of life assessment will be performed pre-surgery and at 90 days.
We will also perform qualitative research with clinical experts and patients to explore
the understanding and experience with the interventions, and adherence to study procedures
and protocol.
Discussion: There have been no randomized control trials that have compared the safety and efficacy
of FFP versus PCC in cardiac surgery in patients who are bleeding. This pilot study
will assess if individual components of a large trial are deliverable to assess the
safety and efficacy of the two blood products in the future.
Trial Registration: PROPHESY has been registered on the EudraCT database (2018-003041-41) and with Clinicaltrials.gov (NCT03715348) on 29 July 2018.
Keywords
Cardiac Surgery, bleeding, Fresh Frozen Plasma, Prothrombin Complex Concentrate, randomized
control trial, pilot study
Background
Approximately 30,000 cardiac procedures are performed each year in the UK, and it
is estimated that approximately 10% of all blood supplied by the national blood service
is used during these procedures. Bleeding after cardiac surgery that requires blood
transfusion is associated with significant morbidity and mortality, resulting in substantial
costs to healthcare systems [1]. The national comparative audit in the UK in 2011,
which incorporated data from 66% of all UK cardiac centres, showed that the overall
blood transfusion rate was high across all procedures, with Fresh Frozen Plasma (FFP)
being administered in over 20% of patients undergoing valve replacement or repair
surgeries, and 30% of patients undergoing combined Coronary Artery Bypass Grafts (CABG)
+ valve repair/replacement surgeries [2].
FFP is the accepted standard treatment for replacement of clotting factors in bleeding
patients undergoing cardiac surgery, yet in a recent Cochrane review only one study,
out of 14 trials (n=738 participants) identified, has evaluated the FFP efficacy in
bleeding patients, and this was underpowered to determine outcomes in mortality [3].
Taking into consideration that blood transfusion is not without risks, other haemostatic
agents, such as Prothrombin Complex Concentrate (PCC) are being explored by clinicians
for management of bleeding, including in the perioperative phase for patients undergoing
cardiac surgery. Potential advantages of PCC over FFP include increased concentration
of clotting factors leading to faster and more sustained reversal of coagulopathy;
improved ease and speed of administration; reduced fluid volume (20 – 40mL compared
to up to 1000mL with FFP); and reduced incidence of immune modulatory side effects.
However, to date there have been no randomized controlled trials (RCT) that have compared
the clinical efficacy and safety of PCC versus FFP in bleeding cardiac surgery patients,
who are not taking vitamin K antagonists (like warfarin), and this was highlighted
in a recent systematic review [4]. Several observational studies have demonstrated
that PCC is safe in this setting, and that its administration is associated with reduced
blood transfusion requirements, albeit with no difference in other outcomes [5, 6].
However, clinical equipoise and the lack of high-quality evidence means that an RCT
is required to determine how PCC compares with FFP. Prior to such a trial, a pilot
study is required to determine if a large scale randomized controlled trial is possible
and this is the hypothesis of this single centre RCT.
Methods
The study design is a single centre (at Barts Health NHS Trust), open label, non-blinded,
pragmatic, pilot randomized control trial (see Figure 1 for study flow chart).
Figure 1:
Study Flowchart
To determine if it is feasible to deliver a large trial in the future that will compare
FFP versus PCC in cardiac surgery patients who are bleeding within 24 hours of surgery.
Evaluate the recruitment rate, defined as the proportion of subjects who consent to
the study (out of all those eligible), and receive the intervention.
Assess the delivery of different components of the trial, assess protocol compliance
and violation, and the ability to collect outcome data.
Compare the impact of FFP and PCC on the haemostatic capacity of bleeding patients,
through the use of standard clotting tests and other global clotting tests,
Obtain input from patients, members of the public and healthcare professionals on
the design/running of the large trial, as well as identify the most important primary/secondary
outcomes for the larger trial.
The proportion of participants who receive intervention within 24 hours of surgery,
out of all eligible participants.
Time to administration of study drug (PCC) or control (FFP) to patient - defined as
time in minutes from telephoning laboratory to first administration to patient.
Proportion of patients for whom clinical outcome data were collected up to 90 days,
or death, whichever occur first
Proportion of patients who consent and randomised within 24 hours of surgery
Proportion of patients who consent and are not randomised within 24 hours of surgery
Proportion of patients for whom timing of administration, and completion of intervention(s)
were documented
Proportion of patients where there was protocol adherence, and protocol violation
Proportion of patients who do not consent to intervention, but agree to consenting
of their de-identified data for up to 24 hours after surgery
Obtain data on event rates in both groups to help estimate the sample size for the
large trial
A total of 50 patients will be randomized over a 15-month period, with a follow-up
at 90 days or death, whichever occurs first. Consent will be obtained from all patients
prior to participation in the trial.
Inclusion criteria: Adult patients (>18years), Able to give consent, Undergoing elective or non-elective
cardiac surgery, excluding procedures given under exclusion criteria,
Exclusion criteria: Unable to consent, Patients refusing blood transfusion for any reason, First time
isolated coronary artery bypass grafts, First time isolated aortic valve replacement (excluding active endocarditis), Thoraco-abdominal surgeries, Minor surgeries that do not involve cardiopulmonary bypass,
use of warfarin within four days, use of direct oral anticoagulants (i.e. dabigaran,
rivaroxban, apixaban or edoxaban) within 48 hrs or 72 hours depending on estimated
glomerular filtration rate, inherited bleeding disorder, pregnancy, known or suspected allergy to FFP, LG-Octaplas
or PCC, known or suspected allergy to heparin, Sodium citrate dihydrate, sodium dihydrogenphosphate dihydrate and Glycine, history of Heparin-induced thrombocytopenia, IgA deficiency with known antibodies against IgA, documented venous thromboembolism in the last three months, documented antiphospholipid
syndrome, severe protein S deficiency, participation in another clinical trial, where the patient has received Investigational
Medicinal Product (IMP) in the last 3 months
For women of childbearing age (<50 years old) a urine pregnancy test will be performed for eligibility purposes. There will be no other study specific screening procedures.
To determine the bleeding rate, routine clinical data will also be collected for up
to 24 hours on: a) eligible participants who have consented to take part in the study,
but are not randomized because they did not develop bleeding; and b) eligible participants
who have not consented to take part in the main study, but have consented to the collection
of de-identified routine data.
The pragmatic nature means that the decision on whether to administer intervention
will be based on clinicians’ judgement, so that when a patient is actively bleeding
within 24 hours of surgery and a clinician has decided that FFP is needed to treat
the bleeding, the patient will be randomized by the transfusion laboratory to either a single dose of FFP (Fresh
Frozen plasma or LG-Octaplas) or 4-factor PCC (Octaplex) using a web-based electronic
database. In the UK it is recommended that individuals born after 1st of January 1996 should be transfused non-UK plasma, as a variant CJD risk reduction
measure and this has been the practice since 1999 [7]. At the study site, LG-Octaplas
is the standard of care for management of such patients who are bleeding. Doses of
intervention will be calculated according to subject weight, and as per the dosing
schedules below:
If the subject continues to bleed after this first single dose of study treatment,
standard care for the treatment of bleeding will continue as per hospital protocol,
and this may include having additional FFP. However, no further PCC will be administered
to subjects.
Subjects will have laboratory assessments with standard routine care tests and thromboelastography
(TEG). Research blood samples will also be taken at 3 time points (pre-intervention,
1 hour and 24 hours post intervention) to perform a more detailed analysis of haemostatic
capacity of subjects (see table 1 under Appendix).
Clinical data that will be collected include: age, gender, ethnicity, previous medical history, drug history, type of surgery, date/time
of intervention. For those who have received intervention, daily and weekly (24 hrs, 7, 14, 21, 30 days, or on discharge, or death – whichever is first) assessments will be performed for: Amount of blood lost through the chest drains, blood components transfused (RBC, RBC,
FFP, Platelets and cryoprecipitate), any other haemostatic agents administered (such
as recombinant Factor VIIa, fibrinogen concentrate), total days in Intensive Care
Unit (level 3); High Dependency Units (Level 2), any organ failure (e.g. acute lung
injury, acute respiratory distress syndrome renal failure, liver failure etc.), thrombosis
(arterial and venous thrombosis), acute transfusion reaction, Infections, duration
of organ support (i.e. ventilatory support, cardiovascular support, and renal replacement
therapy) and mortality. At 90 days, or death – whichever is first the following data will be collected: mortality, re-hospitalization, thromboembolic event (arterial and venous), number
of days alive and out of hospital since operation and QOL questionnaire.
Over a 15-month period, we expect 638 patients to be eligible – this would allow us
to estimate a consent rate of 30% within a 95% confidence interval of +/- 3.5%. Assuming that 30% of the eligible patients consent, we will have a sample of 191 patients
on which to estimate the proportion of consented patients who bleed and are administered
FFP/PCC. From the national and local cardiac audit data, the rate of FFP transfusion in the eligible
study patients is just over 30%, so we have estimated that 30% of consented patients
will go on to develop bleeding during surgery that requires FFP transfusion. A sample
size of 191 would allow us to estimate a proportion of 30% within a 95% confidence
interval of +/- 6.5%. Based on the above 30% rate, around 57 patients would be randomized within 15 months
giving an expected final sample size of 50 patients completing the study after allowing
for 10% drop out or loss to follow up. This sample would be analyzed for assessment of
the secondary endpoints. No formal interim analysis for efficacy is planned. Numbers recruited, eligibility
and consent rates will be considered by the Data Safety Monitoring Committee (DSMC).
Safety analysis including reporting of adverse events will be undertaken biannually
for review by the DSMC. Other interim analysis may be undertaken at the request of
the DSMC. Tables will be prepared by the study statistician.
The primary analysis will use data from the eligible patient population (for consent
rate estimation) and the consenting patients (for estimation of the percentage who
are randomized and receive study treatment). The proportion of patients who agree
to collection of their de-identified data for up to 24 hours after surgery will be
obtained analyzing the population of eligible patients who do not consent to enter
the main trial. The intention-to-treat population will be used to analyze secondary
endpoints relating to the delivery of the intervention, clinical outcome data and
hemostatic capacity of patients. Full details of the statistical considerations are
given in the study Statistical Analysis Plan.
Discussion
There has been no randomized controlled trial (RCT) that has compared the clinical
efficacy and safety of PCC versus FFP in patients undergoing cardiac surgery, who
are bleeding and have not been on a vitamin K antagonist in the perioperative phase.
Observational studies have suggested that PCC is safe in this setting: however, clinical
equipoise and the lack of high-quality evidence mean that a large RCT is required
to determine how PCC compares with FFP. Prior to such a trial, it is important that
feasibility of recruitment, as well as different aspects of delivering the large trial
are assessed, and this is the aim of this pragmatic, pilot randomized control trial.
The pragmatic nature means that the decision on whether to administer intervention
will be based on ‘real-world’ practice, rather than a specific algorithm. One reason for choosing this approach is because it is vital that the results produced from the study are applicable to everyday practice in the future.
Further, a recent RCT phase III trial in a cardiac surgery setting that compared fibrinogen
concentrate with placebo, highlighted some of the challenges with trials using complex
algorithms to administer intervention [8]. Difficulties in implementing such algorithms
during trials can result in a number of shortcomings such as low proportion of patients
being actually randomized, high rate of non-adherence to the study protocol, high
proportion of patients being given intervention when they did not fulfill the study
criteria, and consequently greater costs incurred.
Furthermore, the pragmatic nature of the trial reflects real world current practice
and does not add pre-intervention tests that could delay the issuing of FFP or PCC
in a clinical scenario that requires rapid action. The pilot study will collect pre-intervention
clotting profile data, but this will not be used as entry criteria to allow intervention
to take place. There is no current bedside test with 100% sensitivity and specificity
to identify the need for blood products after cardiac surgery, and as such the trial
reflects real world practice and current clinical judgement. There is no set limit
for the amount of blood loss to define bleeding, as although this is possible with
a closed chest and chest drains on an intensive care unit, this is not possible to
define in the operating room before chest closure when swabs and suction are being
used.
Another important aspect of this pilot trial are the surveys with different experts across disciplines (cardiac surgeons, anaesthetists, intensivists,
transfusion laboratory scientists etc.) and patient and public groups to reach a consensus
on the outcome measures for the large trial. In 2015 Benstoem and colleagues [9] performed a systematic review of the literature to identify the main outcomes that have been measured
in cardiac surgery intervention trials in adult – in this review a total of 121 outcomes identified, which were collapsed into 36 outcome domains. Using
the results of the above review, in 2017 Bentoem and colleagues [10] performed an
international three-round eDelphi exercise to reach a consensus on core outcomes sets
that should be measured and reported, as a minimum, in clinical trials of cardiac surgery trials. Of the 36 outcome variables identified
from the systematic review, the panel reached consensus on four core outcome sets
which were: mortality, Quality of Life, hospitalization, and cerebrovascular complications. Currently in the UK there a national database that collects clinical outcomes for
patients who have undergone cardiac surgery, and of the four core outcome sets agreed in the Delphi consensus [10], Quality of Life
is the only outcome that is not collected by the national database, and of the 36
outcome variables identified from the systematic review [9] a total of seven variables
are collected in the UK. In order to obtain patient and public opinion about the outcome measures for the
large trial, we will conduct surveys with patients and UK healthcare professionals,
using the results of the above Delphi survey and the outcomes measured by the national
database. Further, we will also conduct interviews with patients and clinicians who
have been involved with the study to explore understanding of, and experience with,
the intervention delivered, get their input on how best to optimize recruitment of
participants, and how to improve adherence of the trial protocols. All these will
allow for a more cost-effective and informative trial in the future.
Trial status
Protocol V2.0, 27 November 2018. Start date of subject recruitment: 01 March 2019.
Project recruitment completion date: 30 June 2020
The study was peer-reviewed by three independent experts as part of the BHF funding
application and underwent Barts Heart Centre independent Peer review. The study protocol
has been reviewed by the Barts Cardiovascular Clinical Trials Unit (CVCTU) Scientific
committee and the Blizard Institute, MHRA and NHS Research Ethics Committees.
The Barts Cardiovascular Clinical Trials Unit (CVCTU) will oversee the management
and conduct of the trial, and will be responsible for Pharmacovigilance and safety
reporting, coordination of trial committees, statistical analysis and reporting, and
database management and CRF design. The study Sponsor will be responsible for trial
monitoring. When the research trial is complete, it is a sponsor requirement that
the records are kept for a further 20 years in a secure, long-term storage facility
as per the Sponsor policy.
Data will be captured in REDCap, a web-based electronic database, for all study participants
and the database will be held on a secure server at Queen Mary University of London
(QMUL). Participants eligible for the study will be given a screening number, and
this number will be used to identify them throughout their study duration. The screening
number will be identified on all electronic Case Report Forms (eCRFs) and study documentation,
e.g. questionnaires, lab reports, enrollment and dispensing logs. Only authorized
users approved by the Chief Investigator (CI) will have access to the REDCap electronic
database, and each user will be assigned specific user roles and rights. Sponsor representatives
and CVCTU team members will have read-only access to the data. The study Research
Nurse will be the primary person with delegated responsibility for data entry and
CRF completion. The transfusion laboratory team will have access to the eCRF to complete
randomization. The CI will have overall responsibility for data captured in the eCRF
and be able to review, lock and electronically sign the completed eCRFs.
List of abbreviations
ACT
Activated Clotting Time
APTT
Activated Partial Thromboplastin Time
CABG
Coronary Artery Bypass Graft
CTIMP
Clinical Trial of Investigational Medicinal Product
CVCTU
Cardiovascular Clinical Trials Unit
DSMC
Data Safety Monitoring Committee
EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
IMP
Investigational Medicinal Product
MHRA
Medicines and Healthcare products Regulatory Agency
NHSBT
National Health Service Blood and Transplant
PCC
Prothrombin Complex Concentrates
PI
Principal Investigator
QMUL
Queen Mary University of London
RCT
Randomized Control Trial
REC
Research Ethics Committee
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
TSC
Trial Steering Committee
Declarations
Ethics approval and consent to participate
The trial was granted clinical trials authorization by the Medicines and Healthcare
products Regulatory Authority (MHRA), and has received NHS Research Ethics approval
from the London-Fulham REC (18/LO/1726) and Health Research Authority approval (IRAS
Nr. 250632). All subjects participating in the trial will provide written informed consent.
All relevant data from this study will be submitted to peer review journals for publication
following the termination of the study in line with sponsor trust publication policy.
Data will be captured for all study participants, and no patient identifiable data
will be used in any publications. The sponsor retains the right to review all publications prior to submission or publication.
Responsibility for ensuring accuracy of any publication from this study is delegated
to the Chief Investigator.
Availability of data and material
The datasets used and/or analyzed during the current study will be available from
the Chief Investigator on reasonable request. All data generated or analyzed during
this study will be included in future publications.
. The authors declare that they do not have any competing interests, apart from SA who
has previously completed consultancy work for Octapharma. Financial and competing interests information will be collected and documented over the duration
of the study.
The study is funded by the British Heart Foundation (BHF). The funder has reviewed
the funding application, and will have oversight of study progress, but has no role
in the collection, analysis, and interpretation of data and in writing the manuscript.
LG, NR and BO wrote the manuscript. All authors contributed to the design of the study
and writing of the final manuscript.
We acknowledgement the support of the Joint Research Management Office, Queen Mary
University of London as sponsor for the study. The sponsor’s contacts are as follow:
Joint Research Management Office, 5 Walden Street, London, E1 2EF. Email: [email protected]
The trial is managed and run by Barts Cardiovascular Clinical Trials Unit (CVCTU)
at William Harvey Research Institute, QMUL, a UKCRN registered unit (4). The Barts
CVCTU will be responsible for Pharmacovigilance and safety reporting, coordination
of trial committees, statistical analysis and reporting, and database management and
case report form design. The study Sponsor (QMUL) will be responsible for trial monitoring.
When the research trial is complete, it is a sponsor requirement that the records
are kept for a further 20 years in a secure, long-term storage facility as per the
Sponsor policy.
Trial committees have been established to oversee and monitor the trial conduct and
patient safety.
The Trial Steering Committee (TSC) is chaired by an independent cardiac surgeon (Mr Justin Nowell, St. Georges Hospital), with 3 other independent members (Dr Nick Fletcher, Consultant Anaesthetist, St. Georges Hospital, UK; Dr Nicola Curry,
Consultant Haematologist, Oxford University Hospital NHS Trust, UK; and Mr Steve Stevenson,
Lay representative). The TSC provides overall supervision of the trial, and ensures that it is being
conducted according to the protocol, good clinical practice and relevant regulations.
This committee also monitors trial progress in relation to recruitment, data capture
and completeness, protocol deviations and subject withdrawals. Committee meet every
6 months.
The Data Safety Monitoring Committee (DSMC), is chaired by an independent haematologist (Prof Mike Laffan, Imperial College London, UK), with an independent anesthetist (Dr Paul Diprose, University of Southampton, UK) and statistician (Dr Phil Edwards, London School of Hygiene and Tropical Medicine, UK). The DSMC is responsible for reviewing the trial data throughout the study and assessing
whether there are any safety issues that need to be brought to the attention of the
TSC, or any ethical reasons, why the trial should not continue.
Study data is collected and managed using REDCap (research electronic data capture)
tools [11] hosted at Barts Cancer Centre, QMUL. REDCap (Research Electronic Data Capture)
is a secure, web-based application designed to support data capture for research studies,
providing 1) an intuitive interface for validated data entry; 2) audit trails for
tracking data manipulation and export procedures; 3) automated export procedures for
seamless data downloads to common statistical packages; and 4) procedures for importing
data from external sources [11].
Authors' information (optional)
References
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Appendix
Table1.Assessments for Randomised subjects
Prior to surgery (time 0)
Prior to randomisation – Intervention
One hour post study intervention
Day 90 (discharge/ death)
Screening - Assess eligibility (includes urine pregnancy test)
Assessment by surgical team
Assessment by Anaesthesiologist
Bloods1 - group and screen samples
Bloods1 – Liver and renal function tests
Routine coagulation tests (PT, APTT and fibrinogen) 1
Additional clotting assays2
Thromboelastography (TEG) assessment1
Inform transfusion laboratory of need for FFP
Randomisation & Intervention – PCC or LG-Octaplas/FFP
Time of Intervention (start & stop)
Hospital re-admission since discharge
90 day survival status - End of study form (telephone or clinic visit)
FBC; full blood count; PT: prothrombin time; APTT: activated partial thromboplastin
time; FFP: fresh frozen plasma; PCC: prothrombin complex concentrate; ITU: intensive
care unit; AE: adverse events; SAE: serious adverse events
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